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1.
Biomed Chromatogr ; 34(1): e4695, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31469425

RESUMO

A novel and robust two-dimensional liquid chromatography with ultraviolet detection method (2D-LC-UV) was developed and validated for high-throughput determination of the concentrations of valproic acid (VPA) in human plasma. This 2D-LC system was composed of a first-dimensional LC column, a second-dimensional LC column and an intermediate transfer column. The sample was directly injected into the 2D-LC system after an easy protein precipitation treatment. After online preconcentration and primary separation by the first-dimensional column, the target was captured by an intermediate column and then transferred to second-dimensional column for analysis. The system transferred the target through "central cutting" mode whereby the drug peak was not subject to interference from the matrix. The analysis cycle time was completed within 7.0 min. Compared with other methods that have been developed, the analysis time was reduced and the operation was much easier without any derivatization. The calibration curve was linear over the 5.90-188.94 µg/ml range for the VPA concentrations. The intra-day and inter-day precisions were <5.6%. The recoveries were in the range from 95.2 to 98.0%. This method appears to be sensitive, precise, rapid and low-cost for the quantification of VPA in serum sample.


Assuntos
Cromatografia Líquida/métodos , Ácido Valproico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Ácido Valproico/química , Ácido Valproico/isolamento & purificação , Adulto Jovem
2.
Gen Hosp Psychiatry ; 59: 67-72, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276904

RESUMO

OBJECTIVE: Valproic acid (VPA)-induced hyperammonemia (VIH), is an increase in blood ammonia levels without any alteration of hepatic enzymes, which can occur during VPA treatment. We aimed to determine the prevalence rate and the risk factors for VIH and its association with cognitive functions. METHOD: A prospective, cross-sectional study was conducted. Patients aged between 18 and 64 who were on VPA treatment and who diagnosed with mood disorders or epilepsy were enrolled in this study (n = 107). For cognitive assessment, Serial 7's and Subjective Memory Complaints Questionnaire (SMCQ) were used. Blood samples were collected for blood VPA and ammonia levels along with other laboratory tests. RESULTS: 55,3% of the sample were considered as VIH. Blood ammonia level significantly correlates with VPA blood levels, total daily dose of VPA and total number of medications concurrently used, but no significant correlation was found between blood ammonia level and cognitive test scores. Gender, body weight, blood VPA levels and the total number of medications concurrently used significantly predicted blood ammonia levels (F(4,81) = 2670, p = 0,038, R2 = 0,116). CONCLUSION: VIH is relatively high in our sample. There is a dose-dependent association between VPA and blood ammonia level. No association was found between cognitive functions and hyperammonemia however with some limitations. Future, prospective cohort studies are needed.


Assuntos
Fármacos do Sistema Nervoso Central/efeitos adversos , Disfunção Cognitiva , Epilepsia , Hiperamonemia , Transtornos do Humor , Ácido Valproico/efeitos adversos , Adolescente , Adulto , Fármacos do Sistema Nervoso Central/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/epidemiologia , Estudos Transversais , Epilepsia/tratamento farmacológico , Epilepsia/epidemiologia , Feminino , Humanos , Hiperamonemia/sangue , Hiperamonemia/induzido quimicamente , Hiperamonemia/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/tratamento farmacológico , Transtornos do Humor/epidemiologia , Prevalência , Fatores de Risco , Ácido Valproico/sangue , Adulto Jovem
3.
J Chromatogr A ; 1601: 335-339, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31155143

RESUMO

Sodium valproate is the most commonly used antiepileptic drug that patients need to keep taking over a long period of time or on a permanent basis. Its blood concentration should be accurately detected to avoid toxicity or side-effects, especially for children and the aged. Dried blood spot (DBS) sampling from finger prick is a minimally invasive and patient-friendly procedure for blood collection. However, there are few studies about rapid detection of sodium valproate in DBS samples in current literatures. In this work, we developed an ink auxiliary headspace gas chromatography mass spectrometry (GC-MS) strategy for direct detection of sodium valproate in DBS from epilepsy patients, which does not need extra solvent extraction or elution. It was discovered that carbon black ink could provide better capacity of heat absorption and dissociation, and higher quality of headspace sampling. The detection sensitivity has been improved with reported headspace GC-MS methods, and the limit of quantitation could reach to 200 ng/mL. Finally, this strategy was practically applied to quantify sodium valproate in DBS samples from 29 epilepsy patients. The result showed higher accuracy with lower relative errors by comparing with the clinical immunoassay results. In conclusion, we developed a direct detection method for DBS samples that is suitable for high-throughput clinical test with great potential for clinical application.


Assuntos
Teste em Amostras de Sangue Seco/métodos , Cromatografia Gasosa-Espectrometria de Massas , Ácido Valproico/análise , Anticonvulsivantes/análise , Anticonvulsivantes/sangue , Criança , Monitoramento de Medicamentos , Humanos , Manejo de Espécimes , Ácido Valproico/sangue
4.
Int J Clin Pharm ; 41(4): 1056-1061, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222537

RESUMO

Background Valproic acid is one of several antiepileptic medications requiring therapeutic drug monitoring due to its complex and wide pharmacokinetic interindividual variability. Objective The objective of this study was to determine the population pharmacokinetics of valproic acid in adult Saudi patients and to identify factors that explain its pharmacokinetic variability. Setting Tertiary referral teaching hospital, Riyadh, Saudi Arabia. Method A retrospective chart review was performed at King Saud University Medical City of patients who received oral valproic acid. The population pharmacokinetic models were developed using Monolix 4.4. After development of the base model, we investigated several covariates including age, sex, weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Main outcome measures the pharmacokinetic parameters of valproic acid and the variables that contributing towards its inter-individual variability. Results The analysis included a total of 54 valproic acid plasma concentrations from 54 patients (42.5% male). The data were sufficiently described by a one-compartment model with linear absorption and elimination processes. Average parameter estimates for valproic acid apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.14 L/h and 37.7 L (fixed), respectively. The inter-individual variability (coefficients of variation) in CL/F was 12%. The most significant covariates for valproic acid CL/F were age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin. Conclusion This model showed significant inter-individual variability between subjects. Our findings showed that patient age, body weight, total daily dose, and cotherapy with carbamazepine and phenytoin are the most significant covariates of valproic acid clearance. Collectively, healthcare providers should take these factors in consideration for optimal valproic acid dosage regimen.


Assuntos
Taxa de Depuração Metabólica , Ácido Valproico/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Interações de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Fenitoína/uso terapêutico , Estudos Retrospectivos , Arábia Saudita , Topiramato/uso terapêutico , Ácido Valproico/administração & dosagem , Ácido Valproico/sangue , Adulto Jovem
5.
Drug Test Anal ; 11(7): 1035-1047, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30821115

RESUMO

DP-VPA is a phospholipid prodrug of valproic acid (VPA) that is developed as a potential treatment for epilepsy. To characterize the pharmacokinetics and excretion of DP-VPA, four reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods were validated for quantitation of DP-VPA and its metabolite, VPA, in human plasma, urine, and feces. Protein precipitation and solid-phase extraction (SPE) were used for extraction of C16, C18 homologs of DP-VPA and VPA, respectively, from plasma. Urine and fecal homogenate involving the three analytes were efficiently prepared by methanol precipitation. The determinations of C16 DP-VPA, C18 DP-VPA, and VPA were performed using the positive multiple reaction monitoring (MRM) mode and the negative single ion monitoring (SIM) mode, respectively. The analytes were separated using gradient elution on C8 or phenyl column. Satisfactory results pertaining to selectivity, linearity, matrix effect, accuracy and precision, recovery, stability, dilution integrity, carryover, and incurred sample analysis (ISR) were obtained. The calibration ranges in human plasma were as follows: 0.00200-1.00 µg/mL for C16 DP-VPA, 0.0100-5.00 µg/mL for C18 DP-VPA, and 0.0500-20.0 µg/mL for VPA. The linear ranges in urine and fecal homogenate were 0.00500-2.00 µg/mL and 0.00200-0.800 µg/mL for C16 DP-VPA, 0.00500-2.00 µg/mL and 0.0100-4.00 µg/mL for C18 DP-VPA, and 0.200-80.0 µg/mL for VPA, respectively. The intra- and inter-batch coefficients of variation in three matrices ranged from 1.7% to 12.4% while the accuracy values ranged from 85.4% to 111.7%. The developed methods were successfully applied to determine pharmacokinetics of DP-VPA tablet after a single oral dose of 1200 mg in 12 healthy Chinese subjects under fed condition.


Assuntos
Anticonvulsivantes/farmacocinética , Ácido Valproico/análogos & derivados , Ácido Valproico/farmacocinética , Adulto , Anticonvulsivantes/sangue , Anticonvulsivantes/urina , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Fezes/química , Feminino , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas em Tandem/métodos , Ácido Valproico/sangue , Ácido Valproico/urina , Adulto Jovem
6.
Brain Dev ; 41(6): 516-521, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30827788

RESUMO

OBJECTIVE: This study measured the serum carnitine levels in patients with epilepsy and determined the factors contributing to low carnitine levels. METHODS: We measured the serum carnitine levels in 94 consecutive patients with epilepsy, including the free carnitine (FC) and acylcarnitine fractions, using an enzyme cycling method. We defined a low FC as a serum FC level < 36 µmol/L. Age, body mass index (BMI), standard deviation score of BMI (BMI-SDS), use of valproate, cognitive disorder, and feeding problems differed between patients with low and normal FC. In patients taking valproate, the associations of the serum FC level with the platelet count and serum ammonia and amylase levels were analyzed. RESULTS: Univariate analysis showed that a low BMI and BMI-SDS, the use of valproate, and cognitive disorder were more frequent in patients with a low FC. Logistic regression analysis revealed that a low BMI-SDS and cognitive disorders were independently associated with a low FC. Among the patients taking valproate, a low BMI-SDS and age were associated with a low FC. The serum FC and ammonia levels were inversely correlated, whereas no correlation was observed between the serum FC level and platelet count or serum amylase level. CONCLUSION: A low BMI and cognitive disorders were related to a low FC in patients with epilepsy and the serum carnitine levels should be monitored in these patients.


Assuntos
Carnitina/análise , Epilepsia/metabolismo , Ácido Valproico/análise , Adolescente , Índice de Massa Corporal , Carnitina/análogos & derivados , Carnitina/sangue , Criança , Pré-Escolar , Disfunção Cognitiva/metabolismo , Epilepsia/complicações , Epilepsia/patologia , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Ácido Valproico/sangue , Adulto Jovem
7.
Int Clin Psychopharmacol ; 34(3): 143-150, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30907774

RESUMO

Some women affected by mood disorders experience mood instability during the premenstrual phase. Assuming that fluctuations in drug serum levels may contribute to the worsening of mood symptoms, we carried out a systematic review of available studies that investigated changes in lithium and valproate levels in relation to menstrual phases. We selected five studies; four of which assessed menstrual fluctuations in lithium serum levels and one in valproate levels. Study samples included women in their fertile age affected by bipolar disorder, epilepsy as well as healthy ones. Preliminary results showed a close relationship between cyclic premenstrual exacerbation of affective symptoms and a significant decrease in lithium levels during the luteal phase, despite stable oral doses, in bipolar women. In healthy women, lithium levels were influenced by neither menstrual cycle phases nor oral contraceptives use. Valproate serum levels in epileptic women showed a small, nonsignificant decline during the mid-luteal phase. Pharmacokinetic sex differences in adsorption, volume distribution, hepatic metabolism, and renal excretion of mood stabilizers have been supposed to partly explain such menstrual serum level fluctuations. A better understanding in this field could help to counteract the distress related to premenstrual phase, improving therapeutic management of mood disorders in women.


Assuntos
Afeto/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Lítio/sangue , Ciclo Menstrual/psicologia , Ácido Valproico/sangue , Feminino , Humanos , Masculino , Transtornos do Humor
9.
J Pharm Biomed Anal ; 162: 130-139, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30236821

RESUMO

N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a novel valproic acid derivative that has shown anti-proliferative activity against epitheloid cervix carcinoma (HeLa), rhabdomyosarcoma (A204), and several breast cancer cell lines. The aim of this research was to evaluate the pharmacokinetic profile and tissue distribution of HO-AAVPA in Wistar rats, as well as its human serum albumin binding potential by experimental and in silico methods. A single dose of HO-AAVPA was given to male rats by intravenous, intragastric or intraperitoneal routes at doses of 25, 100, and 100 mg/kg, respectively. Then, blood samples were drawn at predetermined intervals of time, and the HO-AAVPA concentration in the plasma was quantified with a validated HPLC method. The elimination half-life (t1/2) was approximately 222 min, and the systemic clearance (CL) and apparent volume of distribution (Vd) were 2.20 mL/min/kg and 0.70 L/kg, respectively. The absolute oral bioavailability of HO-AAVPA was 33.8%, and the binding rate of HO-AAVPA with rat plasma proteins was between 66.2% and 83.0%. Additionally, in silico, UV and Raman spectroscopy data showed weak interactions between the test compound and human serum albumin. Thus, the results that were obtained demonstrated that despite its low oral bioavailability, the potential anticancer agent HO-AAVPA exhibits acceptable pharmacokinetic properties that would allow it to reach its site of action and exert its pharmacological effect in Wistar Rats, and it has a convenient profile for future assays to evaluate its human applications.


Assuntos
Amidas/farmacocinética , Antineoplásicos/farmacocinética , Pentanos/farmacocinética , Albumina Sérica Humana/metabolismo , Ácido Valproico/farmacocinética , Administração Oral , Amidas/administração & dosagem , Amidas/sangue , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Sítios de Ligação , Disponibilidade Biológica , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pentanos/administração & dosagem , Pentanos/sangue , Ligação Proteica , Ratos Wistar , Distribuição Tecidual , Ácido Valproico/administração & dosagem , Ácido Valproico/sangue
10.
Neurocrit Care ; 30(2): 301-306, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30328046

RESUMO

BACKGROUND: Patient-specific factors can alter the pharmacokinetic disposition of valproic acid. Specifically, the free fraction of valproic acid can increase substantially in patients with hypoalbuminemia or as serum drug concentrations rise due to saturable protein binding. Direct measurement of free serum drug concentrations allows for accurate assessment of drug levels, but the assay may not be readily available in all institutions. The effect of hypoalbuminemia on free fraction has been quantified and serves as the basis of an equation used to "correct" measured total valproic acid concentrations. The aim of this study was to evaluate the accuracy of the equation. METHODS: This retrospective study included adult patients with measurable free and total valproic acid concentrations between July 2014 and June 2017. The primary aim was to assess the relationship between measured and predicted free valproic acid concentrations. Free levels were categorized as subtherapeutic, therapeutic, or supratherapeutic based on the reference range of 7-23 mg/L. Concordance was defined as measured and predicted concentrations falling within the same category. RESULTS: The analysis included 174 patients with a median age of 58 years and a median albumin of 3 g/dL. The majority of patients were hospitalized (88.5%). Concordance occurred in 56.9% of samples. A Spearman's correlation coefficient of 0.60 (p < 0.001) was found between the measured and predicted free valproic acid concentrations. Concordance of concentrations was 42% for ICU patients, 63% for floor patients, and 65% for outpatients. Of those with discordant concentrations, 97% of the predicted concentrations underestimated the measured concentrations. CONCLUSIONS: There is discordance between predicted and measured free serum valproic acid concentrations when using the proposed equation. Because of the potential impact of underestimation and variability of free valproic acid concentrations, a measured free level is the ideal option for therapeutic drug monitoring of valproic acid.


Assuntos
Fármacos do Sistema Nervoso Central/sangue , Hipoalbuminemia/sangue , Neurotransmissores/sangue , Farmacocinética , Albumina Sérica , Ácido Valproico/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Curr Neuropharmacol ; 17(1): 99-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29119932

RESUMO

BACKGROUND: Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, comedication) can transiently alter the enzyme expression and activities resulting in genotypephenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways. METHODS: CYP2C9 mediated oxidation of valproate, which is the minor metabolic pathway in adults, appears to become the principal route in children. Genetic and non-genetic variations in CYP2C9 activity can result in significant inter- and intra-individual differences in valproate pharmacokinetics and valproate induced adverse reactions. RESULTS: The loss-of-function alleles, CYP2C9*2 or CYP2C9*3, display significant reduction in valproate metabolism in children; furthermore, low CYP2C9 expression in patients with CYP2C9*1/*1 genotype also leads to a decrease in valproate metabolizing capacity. Due to phenoconversion, the homozygous wild genotype, expected to be translated to CYP2C9 enzyme with normal activity, is transiently switched into poor (or extensive) metabolizer phenotype. CONCLUSION: Novel strategy for valproate therapy adjusted to CYP2C9-status (CYP2C9 genotype and CYP2C9 expression) is strongly recommended in childhood. The early knowledge of pediatric patients' CYP2C9-status facilitates the optimization of valproate dosing which contributes to the avoidance of misdosing induced adverse reactions, such as abnormal blood levels of ammonia and alkaline phosphatase, and improves the safety of children's anticonvulsant therapy.


Assuntos
Citocromo P-450 CYP2C9/metabolismo , Ácido Valproico/uso terapêutico , Adulto , Fatores Etários , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Vias Biossintéticas , Criança , Citocromo P-450 CYP2C9/genética , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Genótipo , Humanos , Fenótipo , Polimorfismo Genético , Ácido Valproico/sangue , Ácido Valproico/farmacocinética
12.
Biomed Chromatogr ; 33(3): e4440, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30456910

RESUMO

Valproic acid (VPA) pharmacokinetics is highly variable and monitoring of blood levels is necessary to determine its appropriate dosage. This study aimed to establish and validate a novel derivatization method for the determination of VPA. The method was based on the catalytic effect of tetramethylammonium hydroxide using 2,4'-dibromoacetophenone as a derivatization reagent. After derivatization, samples were injected into the HPLC system for analysis. The method showed a good linearity in the range of 1.0-200.7 µg mL-1 , and the limit of quantification was 1 µg mL-1 . All values of the accuracy and relative standard deviations were acceptable for the analyses of biological samples. The recoveries were in the range from 91.6 to 97.4% for VPA with RSD <3.9%. A novel and high conversion-rate derivatization method has been developed and validated for the determination of VPA in human serum. It can be applied to the analysis of VPA in clinic serum samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Compostos de Amônio Quaternário/química , Ácido Valproico/sangue , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Ácido Valproico/química
13.
Drug Test Anal ; 11(5): 730-738, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30426701

RESUMO

Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is an important analytical tool in the systematic toxicological analysis performed in forensic toxicology. However, some important compounds, such as the antiepileptic drug valproate (valproic acid; VPA), cannot be directly detected with positive electrospray ionization (ESI+ ) due to poor ionization. Here we demonstrate an omics-based retrospective analysis for the identification of indirect screening targets for VPA in whole blood with LC-ESI+ -HRMS. Analysis was performed utilizing data acquired across four years from LC-ESI+ -HRMS, with VPA results from a quantitative LC-MS/MS method. The combined data with VPA results were split into an exploration set (n = 68; 28% positive) and a test set (n = 37; 32% positive). Eight indirect targets for VPA were identified in the exploration set. The evaluation of these targets was confirmed with retrospective target analysis of the test set. Using a combination of two out of the eight indirect targets, we attained a sensitivity of 92% (n = 12; VPA concentration range: 4.4-29.7 mg/kg) and 100% specificity (n = 25) for VPA with LC-ESI+ -HRMS. VPA screening targets were identified with retrospective data analysis and could be appended to the existing screening procedure. A sensitive and specific screening with LC-ESI+ -HRMS was achieved with targets corresponding to the sodium adducts of C7 H14 O3 and C8 H14 O3 . Three chromatographic resolved isomer peaks were observed for the latter, and the consistently most intense peak was tentatively identified as 3-hydroxy-4-en-VPA.


Assuntos
Anticonvulsivantes/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Ácido Valproico/sangue , Cromatografia Líquida/métodos , Biologia Computacional/métodos , Humanos , Limite de Detecção
14.
Mol Neurobiol ; 56(5): 3736-3750, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30194517

RESUMO

Prenatal treatment with the antiepileptic drug valproic acid (VPA) is associated with a significant risk of somatic anomalies, neurodevelopmental delays, and 7-10× increase in the incidence of autism spectrum disorders (ASD) in children. Rodents exposed to VPA in pregnancy show birth defects, deficits in neurodevelopment, and cognitive/social anomalies resembling those of ASD children. Mechanisms of VPA neurobehavioral toxicity are still unclear but as VPA is a non-selective inhibitor of histone deacetylases, epigenetic modifications are likely involved. This study was aimed to evaluate the transgenerational impact of prenatal VPA exposure on mouse early behavioral development, studying F1, F2, and F3 generations after VPA challenge on gestational day (GD) 10.5. We also analyzed in brain and in peripheral blood mononuclear cells the expression levels of different endogenous retrovirus (ERV) families, potential biomarkers of derailed brain development, since human ERVs have been implicated in the pathogenesis of neurodevelopmental disorders (NDDs) such as ASD. Somatic effects of VPA were evident only in F1 generation and more markedly in the female sex. Across F1 and F2 generations, VPA delayed righting reflex, increased motor activity, and reduced ultrasonic vocalizations. The behavioral changes in F3 are milder though in the same direction. VPA increased expression of most ERVs across the three generations in brain and blood. In utero VPA induced neurodevelopmental alterations more marked in the maternal lineage that persisted also in F3, suggesting ERVs as possible downstream effectors of the VPA epigenetic alterations.


Assuntos
Comportamento Animal , Retrovirus Endógenos/genética , Padrões de Herança/genética , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/virologia , Ácido Valproico/efeitos adversos , Animais , Encéfalo/patologia , Feminino , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Análise de Componente Principal , Transcrição Genética , Ácido Valproico/sangue
15.
Pak J Pharm Sci ; 31(4(Special)): 1773-1776, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30203778

RESUMO

The unpredictable and unfavorable connection of dose and plasma concentration of valproic acid supports the necessity to regularly measure its plasma concentration. The present study is drug monitoring of valproic acid and comparative evaluation of therapeutic monitoring results of valproic acid for assessment of clinical response, safety and toxicity in different age and gender groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of valproic acid in various sub-groups of epileptic patients for enhancing the safety and minimizing the toxicity of valproic acid. A total of 206 plasma samples (126 males and 80 females) of epileptic patients using valproic acid were requested for therapeutic drug monitoring by neurology department of Qilu Hospital. It was found that 29 % of the total samples were found in sub-therapeutic levels, 13% of the samples had toxic levels and 58% of all the samples had valproic acid levels in therapeutic range. The difference in plasma concentration of valproic acid is notably altered in gender and various age groups. However, this requires further investigation. Despite the majority of samples in the therapeutic range, there was an unfavorable clinical response. The outcomes of the current research work exposed that there was a poor correlation between the plasma concentration and clinical response. Careful attention must be applied to specific gender and particular age group on an individual basis in the interpretation of plasma concentration results, in order to facilitate the modification of doses and develop the best approach in treatment and to obtain the desired clinical response because multiple factors can affect the valproic acid plasma concentration. Through these results, it can be concluded that poor correlation exists between valproic acid plasma concentration and clinical response.


Assuntos
Monitoramento de Medicamentos/estatística & dados numéricos , Ácido Valproico/farmacocinética , Adulto , Fatores Etários , Idoso , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Epilepsia/tratamento farmacológico , Feminino , Humanos , Lactente , Masculino , Fatores Sexuais , Resultado do Tratamento , Ácido Valproico/sangue , Ácido Valproico/uso terapêutico
16.
Ned Tijdschr Geneeskd ; 1622018 08 16.
Artigo em Holandês | MEDLINE | ID: mdl-30212012

RESUMO

BACKGROUND: Valproic acid is one of the most widely prescribed drugs for the treatment of epilepsy and bipolar disorder. As only the unbound fraction of a medicinal product is pharmacologically active, in some strong protein-bound psychotropic drugs such as valproic acid and phenytoin, a rise in this fraction can lead to severe toxicity. CASE DESCRIPTION: A 65-year-old male with a type 1 bipolar disorder developed a number of neurological symptoms including sluggishness, muscle weakness, difficulty in walking and disorders of micturition after his mood stabiliser was changed to valproic acid. Recognition of drug toxicity was delayed as his total plasma valproic acid levels were within the therapeutic range. Later it became apparent that the patient had toxic unbound valproic acid levels due to hypoalbuminaemia and impaired renal function. CONCLUSION: Clinicians should always consider drug toxicity in patients who show neurological symptoms and use highly protein-bound psychotropic drugs, even if the total plasma concentration of the drug is in the therapeutic range.


Assuntos
Anticonvulsivantes/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Hipoalbuminemia/sangue , Doenças do Sistema Nervoso/induzido quimicamente , Ácido Valproico/efeitos adversos , Idoso , Anticonvulsivantes/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/complicações , Humanos , Hipoalbuminemia/complicações , Masculino , Limitação da Mobilidade , Debilidade Muscular/induzido quimicamente , Transtornos Urinários/induzido quimicamente , Ácido Valproico/sangue
18.
Eur J Pharm Sci ; 122: 170-178, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29981400

RESUMO

Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach. For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization.


Assuntos
Anticonvulsivantes/farmacocinética , Epilepsia/genética , Epilepsia/metabolismo , Modelos Biológicos , Receptores para Leptina/genética , Ácido Valproico/farmacocinética , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Anticonvulsivantes/sangue , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Sistema Enzimático do Citocromo P-450/genética , Epilepsia/sangue , Genótipo , Glucuronosiltransferase/genética , Humanos , Lactente , Receptores Citoplasmáticos e Nucleares/genética , Ácido Valproico/sangue
19.
Seizure ; 59: 24-27, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29730272

RESUMO

PURPOSE: To evaluate variables affecting the valproate (VPA) free fraction and develop an equation for computing free VPA concentration from total VPA concentration. METHODS: Trough total and free VPA concentrations were collected from patients who participated in a prospective VPA monotherapy trial. All available paired data of trough total and free VPA concentrations were included. Significant variables from the univariate analysis were evaluated in a multivariate model. RESULTS: A total of 902 concomitant total and free VPA concentrations were available. Multivariate analysis showed that total VPA concentration, age and gender were significantly associated with VPA free fraction. However, the effect size of total VPA concentration was substantially higher than that of gender and age. VPA free fraction remained stable at around 10% for total VPA concentration between 20 and 60 µg/mL with subsequent linear increases for higher concentration. A scatter plot correlating total and free VPA concentrations showed that a quadratic equation best fitted the data, accounting for 88% of the free VPA concentration variance. CONCLUSIONS: An increase in the total VPA concentration results in corresponding linear and non-linear rise in the VPA free fraction and free VPA concentration, respectively. The total daily dose of VPA should be increased in smaller increments whenever a total VPA concentration of 60 µg/mL is reached. When drug monitoring is needed, we recommend measuring the free VPA concentration. If this test is unavailable, and for patients with normal albumin levels, it can be predicted from the total VPA concentration using the generated equation.


Assuntos
Anticonvulsivantes/sangue , Anticonvulsivantes/uso terapêutico , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Ácido Valproico/sangue , Ácido Valproico/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Anticonvulsivantes/efeitos adversos , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Monitoramento de Medicamentos , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Análise Multivariada , Dinâmica não Linear , Fatores Sexuais , Ácido Valproico/efeitos adversos , Adulto Jovem
20.
Eur J Clin Pharmacol ; 74(8): 1029-1036, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29666902

RESUMO

PURPOSE: Valproic acid (VPA) is an important drug in seizure control with great inter-individual differences in metabolism and treatment effect. This study aims to identify the effects of genetic variants on VPA clearance in a population pharmacokinetic (popPK) model in children with epilepsy. METHODS: A total of 325 VPA plasma concentrations from 290 children with epilepsy were used to develop the popPK model by using the nonlinear mixed-effects modeling method. The one-compartment model was established to describe the pharmacokinetics of VPA. Twelve single nucleotide polymorphisms involved in the pharmacokinetics of VPA were identified by MassARRAY system and their effects on VPA clearance were evaluated. RESULTS: In the two final popPK models, inclusion of a combined genotype of four variants (rs1042597, rs28365062, rs4986893, and rs4244285), total daily dose (TDD), and body surface area (BSA) significantly reduced inter-individual variability for clearance over the base model. The inter-individual clearance equals to 0.73 × (TDD/628.92)0.59 × eUGT-CYP for TDD included model and 0.70 × (BSA/0.99)0.57 × eUGT-CYP for BSA included model. The precision of all parameters were acceptable (relative standard error < 32.81%). Bootstrap and visual predictive check results indicated that both two final popPK models were stable with acceptable predictive ability. CONCLUSION: TDD, BSA, and genotype might affect VPA clearance in children. The popPK models may be useful for dosing adjustment in children on VPA therapy.


Assuntos
Citocromo P-450 CYP2C19/genética , Epilepsia/sangue , Glucuronosiltransferase/genética , Ácido Valproico/farmacocinética , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Criança , Citocromo P-450 CYP2C19/metabolismo , Feminino , Genótipo , Glucuronosiltransferase/metabolismo , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Polimorfismo de Nucleotídeo Único/genética , Ácido Valproico/sangue
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